Resistance profile and cross-resistance of HIV-1 among patients failing a non-nucleoside reverse transcriptase inhibitor-containing regimen

Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix"), Lutetia Parisorum, Île-de-France, France
Journal of Medical Virology (Impact Factor: 2.35). 11/2001; 65(3):445-8. DOI: 10.1002/jmv.2055
Source: PubMed


The objectives were to determine the resistance profile and the rate of cross-resistance in HIV-1 infected patients failing an efavirenz or a nevirapine or a nevirapine then efavirenz containing regimens, and to investigate if zidovudine and more generally thymidine analog nucleosides lead to a particular genotypic pattern in nevirapine failing patients. A study was conducted in 104 patients with virological rebound to a non-nucleoside reverse transcriptase inhibitors (NNRTI) regimen (efavirenz n = 39, nevirapine n = 46 and nevirapine then efavirenz n = 19). Genotypic resistance testing was carried out of detectable plasma HIV-1 RNA (> 200 copies/ml). Among the 104 patients studied, only two patients failed to respond to the nevirapine regimen without selection of a NNRTI resistance mutation. All patients failing an efavirenz regimen harboured mutations conferring cross-resistance to nevirapine (K103N, Y188L, G190S). Among patients failing the nevirapine regimen and presenting with NNRTI mutations, 35 (80%) harboured mutations conferring cross-resistance to efavirenz (K101E, K103N, Y188L) and 9 (20%) harboured mutations conferring resistance to nevirapine alone (V106A and Y181C). In patients failing nevirapine then efavirenz therapy, all NNRTI resistance profile led to cross-resistance to all available NNRTIs. Among patients receiving nevirapine, the selection of mutations associated with a cross-resistance to efavirenz was more frequent statistically when a thymidine nucleoside analog (zidovudine or stavudine) was used in the regimen (P = 0.02). In conclusion, 100% of patients developed cross-resistance to nevirapine and efavirenz after treatment by efavirenz and 80% after treatment by nevirapine. The use of a thymidine analog concomitantly with nevirapine leads to the preferential selection of cross-resistance NNRTI mutations.

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    • "Consequently, many children infected with HIV in the late 1990s, who are adolescents today, may have been maintained on single, dual, or other nonsuppressive regimens for years at a time, only to accumulate enormous numbers of resistance mutations to the commonly used classes of ARVs.19 NVP and EFV have been the mainstay of cART in children when prescribed with a two-drug nucleoside reverse transcriptase inhibitor (NRTI) backbone, especially in developing countries. However, the first-generation NNRTIs have a low genetic barrier to resistance, such that upon VF, two signature point mutations, Y181C (NVP) and K103N (EFV), often develop, which have traditionally rendered the entire class of drugs useless.20 ETR has a much higher threshold for the development of resistance than NVP or EFV, requiring three or more of a certain group of ETR resistance-associated mutations (RAMs) to lose efficacy.21 "
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    ABSTRACT: Pediatric patients infected with human immunodeficiency virus (HIV) are now living longer, healthier lives due to the advent of combined antiretroviral (ARV) therapy, including regimens that often contain non-nucleoside reverse transcriptase inhibitors (NNRTIs). However, first-generation NNRTIs such as nevirapine (NVP) and efavirenz (EFV) have a low genetic barrier to resistance, and both drugs can become ineffective with a single viral point mutation. New agents with activity against resistant viral strains must be available to salvage children and adolescents with virologic failure after NNRTI use. One such drug, etravirine, an oral second-generation NNRTI approved for use in the US in heavily treatment-experienced HIV-1-infected adults in 2008, is accumulating data in this younger population. Etravirine became approved by the US Food and Drug Administration in early 2012 to be used in combination with other ARV medications in HIV-1-infected children aged 6 years to <18 years who are failing their regimens with HIV-1 strains resistant to NNRTIs and other ARVs. This approval was largely based on data from a prospective, open-label, phase II clinical trial in this age group prescribed etravirine at 5.2 mg/kg twice daily (up to the adult dose of 200 mg twice daily) in combination with an investigator-selected optimized background regimen. Currently available 48-week follow-up data show complete viral suppression (<50 copies/mL) in 56% of the patients, with relatively few serious adverse events attributed to the drug. Additional studies and case reports from the field suggest its utility in clinical practice. This review is designed to increase the background understanding of this drug in pediatric HIV providers, to lay out the current pediatric data to support its use, and to define its practical role in the treatment of HIV-infected children now and in the future.
    HIV/AIDS - Research and Palliative Care 04/2013; 5:67-73. DOI:10.2147/HIV.S32324
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    • "The efficacy of first-generation non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) is limited by the low genetic barrier to the development of resistance, resulting from the relatively easy selection of single mutations that confer nearly complete cross-resistance [Bacheler et al., 2001; Delaugerre et al., 2001]. Etravirine (ETR) is a diarylpyrimidine NNRTI with a high genetic barrier to the development of resistance and with potential activity against Human immunodeficiency virus type 1 (HIV-1) strains resistant to first-generation NNRTIs [Andries et al., 2004; Vingerhoets et al., 2005]. "
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    ABSTRACT: Etravirine (ETR) is a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) with a high genetic barrier to the development of resistance and with potential activity against Human immunodeficiency virus type 1 (HIV-1) strains resistant to first-generation NNRTIs. The objective of this study was to investigate the prevalence of ETR resistance associated mutations (RAMs) in HIV-1 strains isolated from infected individuals failing efavirenz (EFV), as well as to evaluate possible differences in the distribution of ETR RAMs between subtype B and non-B genetic variants. Nucleotide sequences of the protease and partial reverse transcriptase (RT) coding regions of the pol gene of 55 HIV-1 strains isolated from infected individuals failing EFV on regular follow-up at a reference center in Portugal, were retrospectively analyzed. The most prevalent ETR RAMs observed were L100I, V90I, and K101E, with a prevalence of 16.4% (n = 9), 9.1% (n = 5), and 5.5% (n = 3), respectively. Overall, 47.3% (n = 26) of the nucleotide sequences had at least one ETR RAM: 38.2% (n = 21) had one ETR RAM, 7.3% (n = 4) had two ETR RAMs and 1.8% (n = 1) had three ETR RAMs. No statistically significant differences were found in the distribution of ETR RAMs between subtype B and non-B genetic variants. The results demonstrate that ETR rescue therapy is a viable option in treatment-experienced individuals failing EFV and suggests that ETR may be equally useful in HIV-1 infections caused by different genetic variants.
    Journal of Medical Virology 04/2012; 84(4):551-4. DOI:10.1002/jmv.23232 · 2.35 Impact Factor
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    • "Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active anti-retroviral treatment (HAART) regimens are characterized by a good tolerance of relatively low levels of adherence to therapy, although resistance selection may ensue when adherence drops below the 75% threshold [1,2]. First generation NNRTIs have a low genetic barrier and the K103N mutation is able to confer class resistance after selection [3,4]. As efavirenz (EFV) and nevirapine (NVP) have a much longer plasma half-life than their companion nucleoside reverse transcriptase inhibitors (NRTIs), residual NNRTI monotherapies associated with structured or non-structured therapy interruptions may favor K103N selection. "
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    ABSTRACT: Selection of the K103N mutation is associated with moderately reduced in vitro fitness of HIV. Strains bearing K103N in vivo tend to persist, even in the absence of additional drug pressure, as minority quasispecies, often undetectable in genotyping resistance testing assays, performed at standard conditions. Here, we report on the rapid and long lasting selection of a K103N bearing strain as the dominant quasispecies after very short exposure to efavirenz in vivo. A 55-year-old Caucasian man was switched to efavirenz, zidovudine and lamivudine in February 2003, while on viral suppression in his first-line highly active anti-retroviral treatment regimen. One month later, he reported inconsistent adherence and his viremia level was 5700 c/mL. He did not attend further checkups until September 2005, when his viral load was 181,000 c/mL. The patient reported interrupting his medications approximately three weeks after simplification. The genotyping resistance testing assay was performed both on HIV RNA and HIV DNA from plasma, yielding an identical pattern with the isolate presence of the K103N mutation in the prevalent strain. Persistence of the K103N mutation as a majority quasispecies may ensue after a very short exposure to efavirenz. Our case would therefore suggest that the presence of the K103N mutation should always be ruled out by genotyping resistance testing assays, even after minimal exposures to efavirenz.
    Journal of Medical Case Reports 09/2009; 3(1):9132. DOI:10.4076/1752-1947-3-9132
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